Background: There have been many changes in clinical trials methodology since the introduction of lithium and the beginning of the modern era of psychopharmacology in 1949. The nature and importance of these changes have not been fully addressed to date. As methodological flaws in trials can lead to false-negative or false-positive results, the objective of our study was to evaluate the impact of methodological changes in psychopharmacology clinical research over the past 60 years. Methodology/Principal Findings: We performed a systematic review from 1949 to 2009 on MEDLINE and Web of Science electronic databases, and a hand search of high impact journals on studies of seven major drugs (chlorpromazine, clozapine, risperidone, lithium, fluoxetine and lamotrigine). All controlled studies published 100 months after the first trial were included. Ninety-one studies met our inclusion criteria. We analyzed the major changes in abstract reporting, study design, participants' assessment and enrollment, methodology and statistical analysis. Our results showed that the methodology of psychiatric clinical trials changed substantially, with quality gains in abstract reporting, results reporting, and statistical methodology. Recent trials use more informed consent, periods of washout, intention-to-treat approach and parametric tests. Placebo use remains high and unchanged over time. Conclusions/Significance: Clinical trial quality of psychopharmacological studies has changed significantly in most of the aspects we analyzed. There was significant improvement in quality reporting and internal validity. These changes have increased study efficiency; however, there is room for improvement in some aspects such as rating scales, diagnostic criteria and better trial reporting. Therefore, despite the advancements observed, there are still several areas that can be improved in psychopharmacology clinical trials.